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1 S1 A General Approach to the Enantioselective α-xidation of Aldehydes Via Synergistic Catalysis. Scott P. Simonovich, Jeffrey F. Van umbeck, & David W. C. Macmillan* rck Center for Catalysis at Princeton University, Princeton, New Jersey dmacmill@princeton.edu Supporting Information I. General Information. Commercial reagents were purified prior to use following the guidelines of Perrin and Armarego 1. All solvents were purified according to the method of Grubbs 2, unless otherwise noted. rganic solutions were concentrated under reduced pressure on a Büchi rotary evaporator. Chromatographic purification of products was accomplished using force-flow chromatography on Silicycle silica gel according to the method of Still 3. Thin-layer chromatography (TLC) was performed on Silicycle 250 µm silica gel plates. TLC visualization was performed by ultraviolet light, KMn 4, or CAM stain. All yields and selectivity reported are averages of at least two experimental runs. 1 NMR spectra were recorded on a Bruker 500 (500 Mz) and are referenced relative to residual CDCl 3 proton signals at δ 7.27 ppm or residual C 6 D 6 at δ 7.15 ppm. Data for 1 NMR spectra are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, ap = apparent), integration, coupling constant (z), and assignment. 13 C NMR spectra were recorded on a Bruker 500 (125 Mz) and are referenced relative to CDCl 3 at δ ppm or C 6 D 6 at δ ppm. Data for 13 C NMR are reported in chemical shift. IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm -1 ). igh Resolution Mass spectra were obtained from the 1 Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals; 3rd ed., Pergamon Press, xford, Pangborn, A. B.; Giardello, M. A.; Grubbs, R..; Rosen, R. K.; Timmers, F. J. rganometallics 1996, 15, Still, W. C.; Kahn, M.; Mitra, A. J. J. rg. Chem. 1978, 43, 2923.

2 S2 Princeton University Mass Spectral Facility. igh Pressure Liquid chromatography (PLC) was performed on a ewlett-packard 1100 Series chromatograph using a chiral column (25 cm) and guard column (5 cm) as noted for each compound. ptical rotations were measured on a Jasco P-1010 polarimeter with [α] D values reported in degrees; concentration (c) is in g/100 ml. All aldehyde starting materials were commercially available or prepared from literature procedures not utilizing DMS, as any residual dimethylsulfide inhibited the reaction. II. Enantioselective α-xidation of Aldehydes 20 mol% N N BF 4 R N NBn 10 mol% CuCl 2 acetone, air, -30 o C 24 h R TMP General Procedure for Enantioselective xidation: To an oven dried vial was added catalyst 2 (87.0 mg, 0.20 mmol, 0.2 equiv.), oven-dried 4Å molecular sieves (5 mg), CuCl 2 (13.5 mg, 0.10 mmol, 0.1 equiv.), and acetone (0.6 ml), which was taken from a bench-top solvent bottle and stored over oven-dried 4Å molecular sieves prior to use. Following the subsequent addition of aldehyde (1.0 mmol, 1.0 equiv.), the resulting brown solution was sealed with a septum cap and moved to a -30 o C bath and stirred for 5 min. A solution of TEMP (187.5 mg, 1.20 mmol, 1.2 equiv.) in acetone (0.32 ml) was added dropwise to the reaction mixture. An ambient air inlet line (16G needle attached to rubber tubing) was then pierced through the septum cap and allowed to hang off the side of the cooling bath. After stirring for 24 h, the mixture was diluted with 2 ml of ether and quenched with 2 ml of saturated aqueous N 4 Cl. After the addition of 1 ml of water, the aqueous layer was extracted with ether (2 ml, x3), and the combined organic layers were dried over Na 2 S 4 and concentrated under vacuum. The crude reaction mixture was purified by column chromatography to yield the α-oxyaminated aldehyde.

3 S3 C 2 N 2 4 steps N N N NBn BF 4 Catalyst 2. Benzylation of L-Tryptophan (20.0 g) was accomplished as previously reported by Magnus 4 to yield L-1-benzyl-Tryptophan (27.4 g, 93.1 mmol, 95% yield). To a dried round bottom flask was added the crude L-1-benzyl-Tryptophan (27.4 g, 93.1 mmol, 1.0 equiv.) and (200 ml), and the reaction mixture was cooled to 0 o C. After 10 min., SCl 2 (13.5 ml, mmol, 2.0 equiv.) was added slowly to the vigorously stirring mixture. The resulting slurry was stirred vigorously at room temperature for 40 h, until complete by LCMS. After complete consumption of starting material, the mixture was concentrated under vacuum, and the solid was dissolved in minimal. The crude product was precipitated with ether and hexanes then filtered. The solid ester Cl salt was dried under vacuum and used without further purification. To a round bottom flask were added the crude ester Cl salt (26.1 g, 75.7 mmol, 1.0 equiv.) and methyl amine (40% in, 60 ml), and the resulting solution was stirred overnight at room temperature until complete consumption of starting material was observed by LCMS. The mixture was then concentrated under vacuum, washed with ether, and concentrated again under vacuum. This procedure was performed three times to remove excess methylamine. The crude product was used without further purification. The crude amide Cl salt was then suspended in 200 ml of C 2 Cl 2 and washed with 200 ml of sat. aq. NaC 3. The aqueous layer was extracted with C 2 Cl 2 (2 x 100 ml), and the combined organic layers were dried over Na 2 S 4, filtered, and concentrated under vacuum. The crude, freebased amide (19.0 g, 61.9 mmol, 1.0 equiv.) was added to a dried round bottom flask with TSA 2 (590 mg, 3.09 mmol, 5 mol%), acetone (23 ml, mmol, 5.0 equiv.), and (125 ml). The mixture was stirred at reflux overnight until complete consumption of starting material was observed by LCMS, after which it was cooled to room temperature and concentrated under vacuum. The crude 4 Magnus, P.; Mugrage, B.; DeLuca, M. R.; Cain, G. A. J. Am. Chem. Soc. 1990, 112,

4 S4 catalyst was purified by flash chromatography with silica gel using EtAc as an eluent to yield the freebase catalyst (17.4 g, 50.1 mmol, 51.2 % yield over four steps from L- Tryptophan) as a colorless oil. IR (thin film) , , , , , , , , , , , , , 749.6, 703.3, cm -1 ; 1 NMR (500 Mz, CDCl 3 ) δ: 7.70 (d, 1, J = 8.0 z, Ar), (m, 4, Ar), 7.19 (t, 1, J = 7.0 z, Ar), 7.14 (t, 1, J = 7.5 z, Ar), (m, 3, Ar), (m, 2, NC 2 Ar), 3.86 (t, 1, J = 5.5 z, 1, C(=)C), (m, 2, C 2 Ar), 2.71 (s, 3, NC 3 ), 1.84 (bs, 1, N), 1.26 (s, 3, C 3 ), 1.01 (s, 3, C 3 ); 13 C NMR (125 Mz, CDCl 3 ) δ: (C(=)), (Ar), (Ar), (Ar), (Ar), (Ar), (Ar), (Ar), (Ar), (Ar), (Ar), (Ar), (Ar), 75.5 (C(C 3 ) 2 ), 59.1 (C(=)C), 49.9 (NC 2 Ar), 26.8 (C(C 3 ) 2 ), 25.9 (C 2 Ar), 25.3 (C(C 3 ) 2 ), 25.2 (NC 3 ); RMS (ESI-TF) calculated for C N 3 [M+] + 24 m/z , found [α] D = (c = 1.64, CCl 3 ). The catalyst was then added to a dried round bottom flask with 400 ml of ether and cooled to -78 o C. While stirring vigorously, BF 4 Et 2 (7.0 ml, 51.1 mmol, 1.02 equiv.) was added dropwise, and the cooling bath was removed. The mixture was stirred for 30 minutes, while slowly warming to room temperature, after which it was filtered, and the solid was recrystallized from a mixture of and 1:1 Et 2 : hexanes to yield the catalyst salt as a white solid. TMP (S)-3-phenyl-2-(2,2,6,6-tetramethylpiperidin1-yloxy)propanal. Prepared following the general procedure outlined above using 3-phenylpropionaldehyde (134.2 mg, 1.00 mmol 1.00 equiv.), catalyst 2 (87.0 mg, 0.20 mmol, 0.2 equiv.), TEMP (187.5 mg, 1.20 mmol, 1.20 equiv.), CuCl 2 (13.5 mg, 0.10 mmol, 0.10 equiv.), 4Å molecular seives (5.0 mg), and acetone (0.92 ml). After 24 h the reaction mixture was subjected to the workup procedure outlined in the general procedure and was purified by flash chromatography using 10% Et 2 in hexanes to provide the title compound (251.3 mg, 89% yield, 92% ee) as a colorless liquid. IR (thin film) , , , , , ,

5 S , , , , , , , , , 957.5, 749.1, cm -1 ; 1 NMR (500 Mz, C 6 D 6 ) δ: 9.89 (d, 2, J = 5.0 z, C(=)), (m, 4, Ar), (m, 1, Ar), 4.52 (dd, 1, J = 5.0, 10.0 z, C(=)C), (m, 2, CPh), (m, 6, C(C 3 ) 2 C 2 C 2 C 2 ), (m, 12, NC(C 3 ) 2 ); 13 C NMR (125 Mz, C 6 D 6 ) δ: (C(=)), (Ar), (Ar), (Ar), (Ar), 88.7 (C(=)C), 60.9 (NC(C 3 ) 2 ), 59.8 (NC(C 3 ) 2 ), 40.3 (C(C 3 ) 2 C 2 C 2 C 2 ), 40.2 (C(C 3 ) 2 C 2 C 2 C 2 ), 36.8 (C 2 Ph), 34.5 (NC(C 3 ) 2 ), 33.9 (NC(C 3 ) 2 ), 20.5 (NC(C 3 ) 2 ), 20.3 (NC(C 3 ) 2 ), 17.3 (C(C 3 ) 2 C 2 C 2 C 2 ); RMS (ESI-TF) calculated for C N [M+] + m/z , found [α] 25 D = (c = 1.06, CCl 3 ). The enantiomeric excess was determined from the corresponding alcohol, which was prepared by treating the aldehyde (1.0 equiv.) with NaB 4 (2.0 equiv.) in (0.5 M) at 0 o C and slowly warming to room temperature over 1 h. Upon complete consumption of starting material, the reaction mixture was diluted with C 2 Cl 2 and quenched with saturated aqueous N 4 Cl. After the addition of water, the organic layer was dried over Na 2 S 4 and concentrated under vacuum. The crude mixture was purified by preparative TLC. PLC analysis of the alcohol (D, 1% IPA/hexanes, 1.0 ml/min, 220 nm) indicated 92% ee: t R (major) = 13.2 minutes, t R (minor) = 15.8 minutes. TMP (S)-2-(tetrahydro-2-pyran-4-yl)-2-(2,2,6,6-tetramethylpiperidin1- yloxy)acetaldehyde. Prepared following the general procedure outlined above using 2- (tetrahydro-2-pyran-4-yl)acetaldehyde 5 (128.0 mg, 1.00 mmol 1.00 equiv.), catalyst 2 (87.0 mg, 0.20 mmol, 0.2 equiv.), TEMP (187.5 mg, 1.20 mmol, 1.20 equiv.), CuCl 2 (13.5 mg, 0.10 mmol, 0.10 equiv.), 4Å molecular sieves (5.0 mg), and acetone (0.92 ml). After 24 h the reaction mixture was subjected to the workup procedure outlined in the general procedure and was purified by flash chromatography using 15% Et 2 in 5 Kitbunnadaj, R.; offmann, M.; Fratantoni, S. A.; Bongers, G.; Bakker, R. A.; Wieland, K.; el Jilali, A.; De Esch, I. J. P.; nge, W. M. P. B.; Timmerman,.; Leurs, R. Bioorganic & dical Chemistry 2005, 13, 6309.

6 S6 petroleum ether to provide the title compound (253.3 mg, 90% yield, 95% ee) as a colorless liquid. IR (thin film) , , , , , , , , , , , , , , 989.6, 868.2, 749.9, cm -1 ; 1 NMR (500 Mz, C 6 D 6 ) δ: 9.95 (d, 1, J = 5.0 z, C(=)), 4.06 (dd, 1, J = 10.0 z, J = 5.0 z, C(=)C), (m, 2, C 2 ), (m, 2, C 2 ), (m, 1, C 2 C(C 2 ) 2 ) (m, 2, C 2 C(C 2 ) 2 ), (m, 20, C 2 C(C 2 ) 2 /TMP); 13 C NMR (125 Mz, C 6 D 6 ) δ: (C(=), 90.8 (C(=)C), 67.6 (C 2 ), 67.5(C 2 ), 61.3 (NC(C 3 ) 2 ), 59.9 (NC(C 3 ) 2 ), 40.4 (C(C 3 ) 2 C 2 C 2 C 2 ), 40.1 (C(C 3 ) 2 C 2 C 2 C 2 ), 37.1 (C 2 C(C 2 ) 2 ), 34.6 (NC(C 3 ) 2 ), 34.3 (NC(C 3 ) 2 ), 29.1 (C 2 C(C 2 ) 2 ), 28.6 (C 2 C(C 2 ) 2 ), 20.5 (NC(C 3 ) 2 ), 17.3 (C(C 3 ) 2 C 2 C 2 C 2 ); RMS (ESI-TF) calculated for C N [M+] + 25 m/z , found [α] D = (c = 0.51, CCl 3 ). The enantiomeric excess was determined from the corresponding m-nitrobenzoyl ester, which was prepared by treating the corresponding alcohol (1.0 equiv.) with triethylamine (2.0 equiv.) and m-nitrobenzoyl chloride (1.2 equiv.) in C 2 Cl 2 (0.5 M) at room temperature for 1 h. Upon complete consumption of starting material, the reaction mixture was diluted with C 2 Cl 2 and quenched with water. The organic layer was dried over Na 2 S 4 and concentrated under vacuum. The crude mixture was purified by preparative TLC. PLC analysis of the ester (D, 2.0% IPA/hexanes, 1.0 ml/min, 254 nm) indicated 95% ee: t R (major) = 13.0 minutes, t R (minor) = 14.7 minutes. TMP (S)-3-(3,4-dimethoxyphenyl)-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)propanal. Prepared following the general procedure outlined above using 3-(3,4- dimethoxyphenyl)propanal 6 (194.0 mg, 1.00 mmol 1.00 equiv.), catalyst 2 (87.0 mg, 0.20 mmol, 0.2 equiv.), TEMP (187.5 mg, 1.20 mmol, 1.20 equiv.), CuCl 2 (13.5 mg, 0.10 mmol, 0.10 equiv.), 4Å molecular sieves (5.0 mg), and acetone (0.92 ml). After 24 h the reaction mixture was subjected to the workup procedure outlined in the general procedure 6 Ermolatev, D. S.; Alifanov, V. L.; Rybakov, V. B.; Babaev, E. V.; Van der Eychen, E. V. Synthesis 2008, 13, 2083.

7 S7 and was purified by flash chromatography using 18% EtAc in hexanes to provide the title compound (305.8 mg, 88% yield, 92% ee) as a colorless liquid. IR (thin film) , , , , , , , , , , , , , , , , 957.0, 857.2, 805.2, 756.2, cm -1 ; 1 NMR (500 Mz, C 6 D 6 ) δ: 9.96 (d, 1, J = 5.0 z, C(=)), (m, 2, Ar), 6.65 (d, 1, Ar), (m, 1, C(=)C), 3.58 (s, 3, C 3 ), 3.48 (s, 3, C 3 ) (m, 2, C 2 Ar), (m, 6, C(C 3 ) 2 C 2 C 2 C 2 ), (m, 12, NC(C 3 ) 2 ); 13 C NMR (125 Mz, C 6 D 6 ) δ: (C(=), (Ar), (Ar), (Ar), (Ar), (Ar), (Ar), 89.1 (C(=)C), 60.9 (NC(C 3 ) 2 ), 59.9 (NC(C 3 ) 2 ), 55.5 (C 3 ), 55.5 (C 3 ), 40.3 (C(C 3 ) 2 C 2 C 2 C 2 ), 40.2 (C(C 3 ) 2 C 2 C 2 C 2 ), 36.6 (C 2 Ar), 34.5 (NC(C 3 ) 2 ), 33.9 (NC(C 3 ) 2 ), 20.6 (NC(C 3 ) 2 ), 20.4 (NC(C 3 ) 2 ), 17.4 (C(C 3 ) 2 C 2 C 2 C 2 ); RMS (ESI-TF) calculated for C N [M+] + m/z , found [α] 24 D = (c = 0.50, CCl 3 ). The enantiomeric excess was determined from the corresponding alcohol, which was prepared by treating the aldehyde (1.0 equiv.) with NaB 4 (2.0 equiv.) in (0.5 M) at 0 o C and slowly warming to room temperature over 1 h. Upon complete consumption of starting material, the reaction mixture was diluted with C 2 Cl 2 and quenched with saturated aqueous N 4 Cl. After the addition of water, the organic layer was dried over Na 2 S 4 and concentrated under vacuum. The crude mixture was purified by preparative TLC. PLC analysis of the alcohol (J, 2.0% IPA/hexanes, 1.0 ml/min, 220 nm) indicated 92% ee: t R (minor) = 30.1 minutes, t R (major) = 34.3 minutes. TMP (S)-3-methyl-2-(2,2,6,6-tetramethylpiperidin1-yloxy)butanal. Prepared following the general procedure outlined above using 3-methylbutanal (86.0 mg, 1.00 mmol 1.00 equiv.), catalyst 2 (87.0 mg, 0.20 mmol, 0.2 equiv.), TEMP (187.5 mg, 1.20 mmol, 1.20 equiv.), CuCl 2 (13.5 mg, 0.10 mmol, 0.10 equiv.), 4Å molecular sieves (5.0 mg), and acetone (0.92 ml). After 24 h the reaction mixture was subjected to the workup procedure outlined in the general procedure and was purified by flash chromatography

8 S8 using 3% Et 2 in hexanes to provide the title compound (212.4 mg, 88% yield, 94% ee) as a colorless liquid. IR (thin film) , , , , , , , , , , , , 956.7, 909.0, cm -1 ; 1 NMR (500 Mz, C 6 D 6 ) δ: 9.98 (d, 1, J = 5.0 z, C(=)), 4.06 (dd, 1, J = 5.0 z, J = 5.0 z, C(=)C), (m, 1, C 2 i-pr), (m, 18, TMP), 1.06 (d, 3, J = 5.0 z, C(C 3 ) 2 ) 0.93 (d, 3, J = 5.0 z, C(C 3 ) 2 ); 13 C NMR (125 Mz, C 6 D 6 ) δ: (C(=), 92.2 (C(=)C), 61.1 (NC(C 3 ) 2 ), 59.8 (NC(C 3 ) 2 ), 40.4 (C(C 3 ) 2 C 2 C 2 C 2 ), 40.2 (C(C 3 ) 2 C 2 C 2 C 2 ), 34.6 (NC(C 3 ) 2 ), 34.2 (NC(C 3 ) 2 ), 30.3 (C(C 3 ) 2 ), 20.5 (NC(C 3 ) 2 ), 20.4 (NC(C 3 ) 2 ), 18.7 (C(C 3 ) 2 ), 17.8 (C(C 3 ) 2 ), 17.4 (C(C 3 ) 2 C 2 C 2 C 2 ); RMS (ESI-TF) calculated for C N [M+] + m/z , found [α] 25 D = (c = 0.84, CCl 3 ). The enantiomeric excess was determined from the corresponding m-nitrobenzoyl ester, which was prepared by treating the corresponding alcohol (1.0 equiv.) with triethylamine (2.0 equiv.) and m- nitrobenzoyl chloride (1.2 equiv.) in C 2 Cl 2 (0.5 M) at 0 o C room temperature for 1 h. Upon complete consumption of starting material, the reaction mixture was diluted with C 2 Cl 2 and quenched with water. The organic layer was dried over Na 2 S 4 and concentrated under vacuum. The crude mixture was purified by preparative TLC. PLC analysis of the ester (AD, 1.0% IPA/hexanes, 1.0 ml/min, 254 nm) indicated 94% ee: t R (major) = 8.2 minutes, t R (minor) = 10.2 minutes. NBoc TMP (S)-tert-butyl-4-(2-oxo-1-(2,2,6,6-tetramethylpiperidin1-yloxy)ethyl)piperidie-1- carboxylate. Prepared following the general procedure outlined above using tert-butyl- 4-(2-oxoethyl)piperidine-1-carboxylate (227.0 mg, 1.00 mmol 1.00 equiv.), catalyst 2 (87.0 mg, 0.20 mmol, 0.2 equiv.), TEMP (187.5 mg, 1.20 mmol, 1.20 equiv.), CuCl 2 (13.5 mg, 0.10 mmol, 0.10 equiv.), 4Å molecular sieves (5.0 mg), and acetone (0.92 ml). After 24 h the reaction mixture was subjected to the workup procedure outlined in the general procedure and was purified by flash chromatography using 12% EtAc in hexanes to provide the title compound (319.2 mg, 84% yield, 95% ee) as a colorless

9 S9 liquid. IR (thin film) , , , , , , , , , , , , , , 868.1, cm -1 ; 1 NMR (500 Mz, CDCl 3 ) δ: 9.90 (d, 1, J = 5.0 z, C(=)), 4.15 (ap bs, 2, C 2 N), (m, 1, C(=)C), 2.69 (ap bs, 2, C 2 N), (m, 1, C 2 C(C 2 ) 2 ) (m, 20, C 2 C(C 2 ) 2 /TMP), (m, 11, C 2 C(C 2 ) 2 /C(C 3 ) 3 ); 13 C NMR (125 Mz, CDCl 3 ) δ: (C(=), (NC(=)), 90.2 (C(=)C), 79.5 (C(C 3 ) 3 ), 61.3 (NC(C 3 ) 2 ), 60.0 (NC(C 3 ) 2 ), 40.3 (C(C 3 ) 2 C 2 C 2 C 2 ), 40.0 (C(C 3 ) 2 C 2 C 2 C 2 ), 37.9 (C 2 C(C 2 ) 2 ), 34.5 (NC(C 3 ) 2 ), 34.2 (NC(C 3 ) 2 ), 28.5 (C(C 3 ) 3 ), 27.8 (N(C 2 ) 2 ), 27.4 (C 2 C(C 2 ) 2 ), 20.5 (C(C 3 ) 2 ), 17.1 (C(C 3 ) 2 C 2 C 2 C 2 ); RMS (ESI-TF) calculated for C N 2 [M+] + m/z , found [α] 25 D = (c = 1.04, CCl 3 ). The enantiomeric excess was determined from the corresponding benzoyl ester, which was prepared by treating the corresponding alcohol (1.0 equiv.) with triethylamine (2.0 equiv.) and benzoyl chloride (1.2 equiv.) in C 2 Cl 2 (0.5 M) at 0 o C room temperature for 1 h. Upon complete consumption of starting material, the reaction mixture was diluted with C 2 Cl 2 and quenched with water. The organic layer was dried over Na 2 S 4 and concentrated under vacuum. The crude mixture was purified by preparative TLC. PLC analysis of the ester (D, 1.0% IPA/hexanes, 1.0 ml/min, 233 nm) indicated 95% ee: t R (major) = 10.5 minutes, t R (minor) = 13.7 minutes. TMP NBoc (S)-tert-butyl-3-(3-oxo-2-(2,2,6,6-tetramethylpiperidin1-yloxy)propyl)-1-indole-1- carboxylate. Prepared following the general procedure outlined above using tert-butyl- 3-(3-oxopropyl)-1-indole-1-carboxylate 7 (273.0 mg, 1.00 mmol 1.00 equiv.), catalyst 2 (87.0 mg, 0.20 mmol, 0.2 equiv.), TEMP (187.5 mg, 1.20 mmol, 1.20 equiv.), CuCl 2 (13.5 mg, 0.10 mmol, 0.10 equiv.), 4Å molecular sieves (5.0 mg), and acetone (0.92 ml). After 24 h the reaction mixture was subjected to the workup procedure outlined in the general procedure and was purified by flash chromatography using 5% EtAc in hexanes 7 Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027.

10 S10 to provide the title compound (353.5 mg, 83% yield, 93% ee) as a colorless liquid. IR (thin film) , , , , , , , , , , , , , 856.6, 764.8, 743.6, cm -1 ; 1 NMR (500 Mz, C- DCl 3 ) δ: 9.87 (d, 1, J = 5.0 z, C(=)), 8.16 (bs, 1, Ar), (m, 2, Ar), (m, 2, Ar), (m, 1, C(=)C), 3.18 (apd, 2, J = 5.0 z, C 2 Ar), 1.69 (s, 9, C(C 3 ) 3 ), (m, 6, C(C 3 ) 2 C 2 C 2 C 2 ), (m, 12, NC(C 3 ) 2 ); 13 C NMR (125 Mz, CDCl 3 ) δ: (C(=), (NC(=)), (Ar), (Ar), (Ar), (Ar), (Ar), (Ar), (Ar), (Ar), 87.5 (C(=)C), 83.5 (C(=)C(C 3 ) 3 ), 60.7 (NC(C 3 ) 2 ), 60.0 (NC(C 3 ) 2 ), 40.1 (C(C 3 ) 2 C 2 C 2 C 2 ), 40.1 (C(C 3 ) 2 C 2 C 2 C 2 ), 34.3 (NC(C 3 ) 2 ), 33.9 (NC(C 3 ) 2 ), 28.2 (C(=)C(C 3 ) 3 ), 25.9 (C 2 Ar), 20.6 (NC(C 3 ) 2 ), 20.4 (NC(C 3 ) 2 ), 17.1 (C(C 3 ) 2 C 2 C 2 C 2 ) ; RMS (ESI-TF) calculated for C N 2 [M+] + 24 m/z , found [α] D = (c = 1.04, CCl 3 ). The enantiomeric excess was determined from the corresponding alcohol, which was prepared by treating the aldehyde (1.0 equiv.) with NaB 4 (2.0 equiv.) in (0.5 M) at 0 o C and slowly warming to room temperature over 1 h. Upon complete consumption of starting material, the reaction mixture was diluted with C 2 Cl 2 and quenched with saturated aqueous N 4 Cl. After the addition of water, the organic layer was dried over Na 2 S 4 and concentrated under vacuum. The crude mixture was purified by preparative TLC. PLC analysis of the alcohol (J, 3% IPA/hexanes, 1.0 ml/min, 226 nm) indicated 93% ee: t R (major) = 11.5 minutes, t R (minor) = 15.0 minutes. TMP (S)-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)pent-4-enal (19). Prepared following the general procedure outlined above using 4-pentenal (84.0 mg, 1.00 mmol 1.00 equiv.), catalyst 2 (87.0 mg, 0.20 mmol, 0.2 equiv.), TEMP (187.5 mg, 1.20 mmol, 1.20 equiv.), CuCl 2 (13.5 mg, 0.10 mmol, 0.10 equiv.), 4Å molecular sieves (5.0 mg), and acetone (0.92 ml). After 24 h the reaction mixture was subjected to the workup procedure outlined in the general procedure and was purified by flash chromatography using 5%

11 S11 EtAc in hexanes to provide the title compound (185.7 mg, 78% yield, 92% ee) as a colorless liquid. IR (thin film) , , , , , , , , , , , , 990.2, 957.8, 919.2, 785.3, cm -1 ; 1 NMR (500 Mz, C 6 D 6 ) δ: 9.86 (d, 1, J = 5.0 z, C(=)), 5.82 (ddt, J AB = 7.5 z, J AC = 11.0 z, J BD = 7.0 z, J BE = 3.0 z, C 2 CC 2 ), (m, 2, C 2 CC 2 ), 4.31 (ddd, 1, J AB = 4.0 z, J AC = 5.0 z, J BD = 3.0 z, C(=)C), (m, 2, C 2 CC 2 ), (m, 18, TMP); 13 C NMR (125 Mz, C 6 D 6 ) δ: (C(=), (C 2 CC 2 ), (C 2 CC 2 ), 88.2 (C(=)C), 60.6 (NC(C 3 ) 2 ), 59.9 (NC(C 3 ) 2 ), 40.3 (C(C 3 ) 2 C 2 C 2 C 2 ), 40.2 (C(C 3 ) 2 C 2 C 2 C 2 ), 35.0 (C 2 CC 2 ), 34.4 (NC(C 3 ) 2 ), 34.0 (NC(C 3 ) 2 ), 20.4 (C(C 3 ) 2 ), 20.3 (C(C 3 ) 2 ), 17.4 (C(C 3 ) 2 C 2 C 2 C 2 ); RMS (ESI-TF) calculated for C N [M+] + m/z , found [α] 24 D = (c = 0.96, CCl 3 ). The enantiomeric excess was determined from the corresponding m-nitrobenzoyl ester, which was prepared by treating the corresponding alcohol (1.0 equiv.) with triethylamine (2.0 equiv.) and m- nitrobenzoyl chloride (1.2 equiv.) in C 2 Cl 2 (0.5 M) at 0 o C room temperature for 1 h. Upon complete consumption of starting material, the reaction mixture was diluted with C 2 Cl 2 and quenched with water. The organic layer was dried over Na 2 S 4 and concentrated under vacuum. The crude mixture was purified by preparative TLC. PLC analysis of the ester (AD, 0.2% IPA/hexanes, 0.8 ml/min, 254 nm) indicated 92% ee: t R (major) = 19.5 minutes, t R (minor) = 22.7 minutes. TMP (S)-2-(2,2,6,6-tetramethylpiperidin1-yloxy)octanal. Prepared following the general procedure outlined above using octanal (128.2 mg, 1.00 mmol 1.00 equiv.), catalyst 2 (87.0 mg, 0.20 mmol, 0.2 equiv.), TEMP (187.5 mg, 1.20 mmol, 1.20 equiv.), CuCl 2 (13.5 mg, 0.10 mmol, 0.10 equiv.), 4Å molecular sieves (5.0 mg), and acetone (0.92 ml) at -40 o C. After 24 h the reaction mixture was subjected to the workup procedure outlined in the general procedure and was purified by flash chromatography using 3% Et 2 in hexanes to provide the title compound (291.9 mg, 86% yield, 90% ee) as a

12 S12 colorless liquid. IR (thin film) , , , , , , , , , , , 972.6, 958.0, 917.5, 784.5, cm -1 ; 1 NMR (500 Mz, C 6 D 6 ) δ: 9.91 (d, 1, J = 5.0 z, C(=)), (m, 1, C(=)C), (m, 1, C(=)CC 2 ), (m, 1, C(=)CC 2 ), (m, 26, C 2 C 2 C 2 C 2 C 3 /TMP), 0.97 (t, 3, J = 5.0 z, C 3 ); 13 C NMR (125 Mz, C 6 D 6 ) δ: (C(=), 89.0 (C(=)C), 60.6 (NC(C 3 ) 2 ), 59.8 (NC(C 3 ) 2 ), 40.3 (C(C 3 ) 2 C 2 C 2 C 2 ), 40.2 (C(C 3 ) 2 C 2 C 2 C 2 ), 34.5 (NC(C 3 ) 2 ), 34.5 (NC(C 3 ) 2 ), 31.9 (C 2 ), 30.2 (C 2 ), 29.7 (C 2 ), 24.6 (C 2 ), 22.9 (C 2 ), 20.5 (NC(C 3 ) 2 ), 20.3 (NC(C 3 ) 2 ), 17.4 (C(C 3 ) 2 C 2 C 2 C 2 ), 14.3 (C 3 ); RMS (ESI-TF) calculated for C N [M+] + m/z , found [α] 26 D = (c = 0.73, CCl 3 ). The enantiomeric excess was determined from the corresponding m-nitrobenzoyl ester, which was prepared by treating the corresponding alcohol (1.0 equiv.) with triethylamine (2.0 equiv.) and m-nitrobenzoyl chloride (1.2 equiv.) in C 2 Cl 2 (0.5 M) at 0 o C room temperature for 1 h. Upon complete consumption of starting material, the reaction mixture was diluted with C 2 Cl 2 and quenched with water. The organic layer was dried over Na 2 S 4 and concentrated under vacuum. The crude mixture was purified by preparative TLC. PLC analysis of the ester (D, 0.5% IPA/hexanes, 0.8 ml/min, 254 nm) indicated 90% ee: t R (major) = 14.8 minutes, t R (minor) = 16.4 minutes. TMP SPh (S)-4-(phenylthiol)-2-(2,2,6,6-tetramethylpiperidin1-yloxy)butanal. Prepared following the general procedure outlined above using 4-(phenylthio)butanal 8 (180.1 mg, 1.00 mmol 1.00 equiv.), catalyst 2 (87.0 mg, 0.20 mmol, 0.2 equiv.), TEMP (187.5 mg, 1.20 mmol, 1.20 equiv.), CuCl 2 (13.5 mg, 0.10 mmol, 0.10 equiv.), 4Å molecular sieves (5.0 mg), and acetone (0.92 ml). After 24 h the reaction mixture was subjected to the workup procedure outlined in the general procedure and was purified by flash chromatography using 7% EtAc in hexanes to provide the title compound (288.1 mg, 86% yield, 91% ee) as a colorless liquid. IR (thin film) , , , , , , , , , , , , 957.7, 738.1, cm -1 ; 8 Tius, M. A.; Trehan, S. J. rg. Chem. 1986, 51, 765.

13 S13 1 NMR (500 Mz, C 6 D 6 ) δ: 9.88 (d, 1, J = 5.0 z, C(=)), 7.39 (d, 2, J = 5.0 z, Ar), (m, 2, Ar), (m, 1, Ar), (m, 1, C(=)C), 2.91 (t, 2, J = 7.5 z, C 2 SPh), (m, 1, C(=)CC 2 ), (m, 1, C(=)CC 2 ), (m, 6, C(C 3 ) 2 C 2 C 2 C 2 ), (m, 12, NC(C 3 ) 2 ); 13 C NMR (125 Mz, C 6 D 6 ) δ: (C(=), (Ar), (Ar), (Ar), (Ar), 87.3 (C(=)C), 60.6 (NC(C 3 ) 2 ), 59.9 (NC(C 3 ) 2 ), 40.3 (C(C 3 ) 2 C 2 C 2 C 2 ), 40.2 (C(C 3 ) 2 C 2 C 2 C 2 ), 34.3 (NC(C 3 ) 2 ), 34.1 (NC(C 3 ) 2 ), 30.2 (C 2 SPh), 28.8 (C(=)CC 2 ), 20.4 (C(C 3 ) 2 ), 20.3 (C(C 3 ) 2 ), 17.3 (C(C 3 ) 2 C 2 C 2 C 2 ); RMS (ESI-TF) calculated for C NS [M+] + m/z , found [α] 26 D = (c = 0.60, CCl 3 ). The enantiomeric excess was determined from the corresponding m-nitrobenzoyl ester, which was prepared by treating the corresponding alcohol (1.0 equiv.) with triethylamine (2.0 equiv.) and m- nitrobenzoyl chloride (1.2 equiv.) in C 2 Cl 2 (0.5 M) at 0 o C room temperature for 1 h. Upon complete consumption of starting material, the reaction mixture was diluted with C 2 Cl 2 and quenched with water. The organic layer was dried over Na 2 S 4 and concentrated under vacuum. The crude mixture was purified by preparative TLC. PLC analysis of the ester (D, 1.0% IPA/hexanes, 1.0 ml/min, 254 nm) indicated 91% ee: t R (major) = 18.7 minutes, t R (minor) = 21.0 minutes. TMP Bn (S)-3-(benzyloxy)-2-(2,2,6,6-tetramethylpiperidin1-yloxy)propanal. Prepared following the general procedure outlined above using 3-(benzyloxy)propanal 9 (164.0 mg, 1.00 mmol 1.00 equiv.), catalyst 2 (87.0 mg, 0.20 mmol, 0.2 equiv.), TEMP (187.5 mg, 1.20 mmol, 1.20 equiv.), CuCl 2 (13.5 mg, 0.10 mmol, 0.10 equiv.), 4Å molecular sieves (5.0 mg), and ethyl acetate (0.92 ml). After 24 h the reaction mixture was subjected to the workup procedure outlined in the general procedure and was purified by flash chromatography using 3% Et 2 in toluene to provide the title compound (247.3 mg, 77% 9 Fonvielle, M.; Coincon, M.; Daher, R.; Desbenoit, N.; Kosieradzkak.; Barilone, N.; Gicquel, B.; Sygusch, J.; Jackson, M.; Therisod, M. Chem. Eur. J. 2008, 14, 852.

14 S14 yield, 90% ee) as a colorless liquid. IR (thin film) , , , , , , , , , , , , , , 959.3, 747.8, cm -1 ; 1 NMR (500 Mz, C 6 D 6 ) δ: (d, 1, J = 5.0 z, C(=)), (m, 2, Ar), (m, 2, Ar), (m, 1, Ar), (m, 1, C(=)C), 4.34 (ap s, 2, C 2 Bn), (m, 2, C 2 Ph), (m, 18, TMP); 13 C NMR (125 Mz, C 6 D 6 ) δ: (C(=), (Ar), (Ar), (Ar), (Ar), 89.1 (C(=)C), 73.4 (C 2 Bn), 69.7 (C 2 Ph), 60.3 (NC(C 3 ) 2 ), 60.3 (NC(C 3 ) 2 ), 40.3 (C(C 3 ) 2 C 2 C 2 C 2 ), 40.3 (C(C 3 ) 2 C 2 C 2 C 2 ), 34.2 (NC(C 3 ) 2 ), 33.8 (NC(C 3 ) 2 ), 20.5 (C(C 3 ) 2 ), 20.4 (C(C 3 ) 2 ), 17.4 (C(C 3 ) 2 C 2 C 2 C 2 ); RMS (ESI-TF) calculated for C N [M+] + m/z , found [α] 23 D = (c = 0.73, CCl 3 ). The enantiomeric excess was determined from the corresponding alcohol after formation of the benzyl ester. This compound was prepared by treating the corresponding alcohol (1.0 equiv.) with triethylamine (2.0 equiv.), benzoyl chloride (1.2 equiv.), and DMAP (5 mol%) in C 2 Cl 2 (0.5 M) at 0 o C room temperature for 1 h. Upon complete consumption of starting material, the reaction mixture was diluted with C 2 Cl 2 and quenched with water. The organic layer was dried over Na 2 S 4 and concentrated under vacuum. The crude mixture was purified by flash chromatography. The ester was then treated with Zn (10 equiv.) and a 1:1 Ac/ 2 mixture (0.5M) at 50 o C to cleave the N- bond. The mixture was cooled to room temperature and extracted with C 2 Cl 2, and the organic layer was washed with sat. aq. NaC 3. The organic layer was then dried over Na 2 S 4, filtered, and concentrated under vacuum. The crude mixture was purified by preparative TLC. PLC analysis of the alcohol (AS, 10% IPA/hexanes, 1.0 ml/min, 233 nm) indicated 90% ee: t R (major) = 14.2 minutes, t R (minor) = 17.0 minutes. TMP C 2 Et (S)-ethyl-6-oxo-5-(2,2,6,6-tetramethylpiperidin1-yloxy)hexanoate. Prepared following the general procedure outlined above using ethyl-6-oxohexanoate 10 (158.2 mg, 1.00 mmol 10 Wilson, J. E.; Casarez, A. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131,

15 S equiv.), catalyst 2 (87.0 mg, 0.20 mmol, 0.2 equiv.), TEMP (187.5 mg, 1.20 mmol, 1.20 equiv.), CuCl 2 (13.5 mg, 0.10 mmol, 0.10 equiv.), 4Å molecular sieves (5.0 mg), and acetone (0.92 ml) at -40 o C. After 24 h the reaction mixture was subjected to the workup procedure outlined in the general procedure and was purified by flash chromatography using 8% Et 2 in hexanes to provide the title compound (255.8 mg, 82% yield, 89% ee) as a colorless liquid. IR (thin film) , , , , , , , , , , , , , 958.0, 877.6, 785.9, cm -1 ; 1 NMR (500 Mz, C 6 D 6 ) δ: 9.85 (d, 1, J = 4.5 z, C(=)), (m, 1, C(=)C), 4.04 (q, 2, J = 7.5, 14.5, 21.5 z, C(=)C 2 C 3 ), (m, 2, C 2 C(=)C 2 C 3 ), (m, 4, C 2 C 2 ), (m, 18, TMP), 1.06 (t, 3, J = 7.0 z, C(=)C 2 C 3 ); 13 C NMR (125 Mz, C 6 D 6 ) δ: (C(=), (C(=)C 2 C 3 ), 88.6 (C(=)C), 60.6 (NC(C 3 ) 2 ), 60.1 (C(=)C 2 C 3 ), 59.8 (NC(C 3 ) 2 ), 40.3 (C(C 3 ) 2 C 2 C 2 C 2 ), 40.2 (C(C 3 ) 2 C 2 C 2 C 2 ), 34.4 (NC(C 3 ) 2 ), 34.0 (C 2 C(=)C 2 C 3 ), 33.9 (NC(C 3 ) 2 ), 29.5 (C 2 ), 20.5 (C(C 3 ) 2 ), 20.3 (C(C 3 ) 2 ), 20.2 (C 2 ), 17.4 (C(C 3 ) 2 C 2 C 2 C 2 ) 14.3 (C 2 C 3 ); RMS (ESI-TF) calculated for C N [M+] + m/z , 23 found [α] D = (c = 1.17, CCl 3 ). The enantiomeric excess was determined from the corresponding m-nitrobenzoyl ester, which was prepared by treating the corresponding alcohol (1.0 equiv.) with triethylamine (2.0 equiv.) and m-nitrobenzoyl chloride (1.2 equiv.) in C 2 Cl 2 (0.5 M) at 0 o C room temperature for 1 h. Upon complete consumption of starting material, the reaction mixture was diluted with C 2 Cl 2 and quenched with water. The organic layer was dried over Na 2 S 4 and concentrated under vacuum. The crude mixture was purified by preparative TLC. PLC analysis of the alcohol (J, 1.0% Et/hexanes, 0.8 ml/min, 254 nm) indicated 89% ee: t R (major) = 24.0 minutes, t R (minor) = 30.0 minutes. TMP N(Phth) (S)-6-(1,3-dioxoisoindolin-2-yl)-2-(2,2,6,6-tetramethylpiperidin1-yloxy)hexanal. Prepared following the general procedure outlined above using 6-(1,3-dioxoisoindolin-2-

16 S16 yl)hexanal 11 (245.0 mg, 1.00 mmol 1.00 equiv.), catalyst 2 (87.0 mg, 0.20 mmol, 0.2 equiv.), TEMP (187.5 mg, 1.20 mmol, 1.20 equiv.), CuCl 2 (13.5 mg, 0.10 mmol, 0.10 equiv.), 4Å molecular sieves (5.0 mg), and acetone (0.92 ml). After 24 h the reaction mixture was subjected to the workup procedure outlined in the general procedure and was purified by flash chromatography using 15% EtAc in hexanes to provide the title compound (345.8 mg, 86% yield, 90% ee) as a colorless liquid. IR (thin film) , , , , , , , , , , , , , , , 999.5, 892.3, 791.3, cm -1 ; 1 NMR (500 Mz, C 6 D 6 ) δ: 9.83 (d, 1, J = 5.0 z, C(=)), (m, 2, Ar), (m, 2, Ar), (m, 1, C(=)C), 3.56 (t, 2, J = 7.5 z, C 2 NAr), (m, 1, C(=)CC 2 ), (m, 3, C(=)CC 2 /C 2 ), (m, 20, C 2 /TMP); 13 C NMR (125 Mz, C 6 D 6 ) δ: (C(=), (Ar), (Ar), (Ar), (Ar), (Ar), (Ar), 88.5 (C(=)C), 60.7 (NC(C 3 ) 2 ), 59.7 (NC(C 3 ) 2 ), 40.3 (C(C 3 ) 2 C 2 C 2 C 2 ), 40.2 (C(C 3 ) 2 C 2 C 2 C 2 ), 37.5 (C 2 NAr), 34.5 (NC(C 3 ) 2 ), 34.0 (NC(C 3 ) 2 ), 29.4 (C 2 ), 28.7 (C 2 ), 21.9 (C 2 ), 20.5 (C(C 3 ) 2 ), 20.3 (C(C 3 ) 2 ), 17.4 (C(C 3 ) 2 C 2 C 2 C 2 ); RMS (ESI-TF) calculated for C N 2 [M+] + m/z , found [α] 25 D = (c = 0.91, CCl 3 ). The enantiomeric excess was determined from the corresponding alcohol, which was prepared by treating the aldehyde (1.0 equiv.) with NaB 4 (1.0 equiv.) in (0.5 M) at -78 o C and slowly warming to room temperature overnight. Upon complete consumption of starting material, the reaction mixture was diluted with C 2 Cl 2 and quenched with saturated aqueous N 4 Cl. After the addition of water, the organic layer was dried over Na 2 S 4 and concentrated under vacuum. The crude mixture was purified by preparative TLC. PLC analysis of the alcohol (AD, 3.0% IPA/hexanes, 0.7 ml/min, 220 nm) indicated 90% ee: t R (major) = 46.4 minutes, t R (minor) = 52.2 minutes. TMP (2S,3S)-3,7-dimethyl-2-(2,2,6,6-tetramethylpiperidin1-yloxy)oct-6enal. Prepared 11 Vaismaa, M. J. P.; Yau, S. C.; Tomkinson, N. C.. Tetrahedron Lett. 2009, 50, 3625.

17 S17 following the general procedure outlined above using (S)-Citronellal (154.0 mg, 1.00 mmol 1.00 equiv.), catalyst 2 (87.0 mg, 0.20 mmol, 0.2 equiv.), TEMP (187.5 mg, 1.20 mmol, 1.20 equiv.), CuCl 2 (13.5 mg, 0.10 mmol, 0.10 equiv.), 4Å molecular sieves (5.0 mg), and acetone (0.92 ml). After 24 h the reaction mixture was subjected to the workup procedure outlined in the general procedure and was purified by flash chromatography using 5% Et 2 in hexanes to provide the title compound (246.7 mg, 80% yield, >20:1 dr) as a colorless liquid. IR (thin film) , , , , , , , , , 046.4, 974.7, 957.4, 915.7, cm -1 ; 1 NMR (500 Mz, C- 6D 6 ) δ: (d, 1, J = 5.0 z, C(=)), (m, 1, C 2 CC(C 3 ) 2 ), 4.22 (dd, 1, J = 6.0 z, J = 5.0 z, C(=)C), (m, 3, C(C 3 )C 2 /C 2 CC(C 3 ) 2 ), (m 4, C 3 /C 2 ), 1.68 (s, 3, C 3 ), (m, 19, C 2 /TMP), 1.01 (d, 3, J = 10.0 z, C(C 3 )C 2 ); 13 C NMR (125 Mz, C 6 D 6 ) δ: (C(=), (C 2 CC(C 3 ) 2 ), (C 2 CC(C 3 ) 2 ), 91.3 (C(=)C), 60.9 (NC(C 3 ) 2 ), 60.0 (NC(C 3 ) 2 ), 40.4 (C(C 3 ) 2 C 2 C 2 C 2 ), 40.2 (C(C 3 ) 2 C 2 C 2 C 2 ), 35.1 (CC(C 3 )C 2 ), 34.6 (NC(C 3 ) 2 ), 34.1 (NC(C 3 ) 2 ), 33.1 (C 2 CC(C 3 ) 2 ), 25.9 (CC(C 3 ) 2 ), 25.7 (C 2 ), 20.6 (C(C 3 ) 2 ), 20.5 (C(C 3 ) 2 ), 17.8 (C(C 3 ) 2 ), 17.4 (C(C 3 ) 2 C 2 C 2 C 2 ), 15.1 (C(C 3 )C 2 ); RMS (ESI-TF) calculated for C N [M+] + m/z , found [α] 26 D = (c = 0.65, CCl 3 ). The diastereomeric ratio (>20:1) was determined from the crude 1 NMR aldehyde peaks. TMP (2S,3R)-3,7-dimethyl-2-(2,2,6,6-tetramethylpiperidin1-yloxy)oct-6enal. 12 Prepared following the general procedure outlined above using (R)-Citronellal (154.0 mg, 1.00 mmol 1.00 equiv.), catalyst 2 (87.0 mg, 0.20 mmol, 0.2 equiv.), TEMP (187.5 mg, 1.20 mmol, 1.20 equiv.), CuCl 2 (13.5 mg, 0.10 mmol, 0.10 equiv.), 4Å molecular sieves (5.0 mg), and acetone (0.92 ml). After 24 h the reaction mixture was subjected to the workup procedure outlined in the general procedure and was purified by flash chromatography 12 The comericially available (R)-Citronellal (TCI) was sold as 93% ee, so chiral preprative PLC was used to obtain enantiomeric pure starting material.

18 S18 using 5% Et 2 in hexanes to provide the title compound (249.5 mg, 81% yield, 15:1 dr) as a colorless liquid. Major: IR (thin film) , , , , , , , , , , , 974.9, 957.3, 913.8, cm -1 ; 1 NMR (500 Mz, C 6 D 6 ) δ: (d, 1, J = 5.0 z, C(=)), (m, 1, C 2 CC(C 3 ) 2 ), (m, 1, C(=)C), (m, 3, C(C 3 )C 2 /C 2 CC(C 3 ) 2 ), (m 4, C 3 /C 2 ), 1.66 (s, 3, C 3 ), (m, 19, C 2 /TMP), 1.10 (d, 3, J = 10.0 z, C(C 3 )C 2 ); 13 C NMR (125 Mz, C 6 D 6 ) δ: (C(=), (C 2 CC(C 3 ) 2 ), (C 2 CC(C 3 ) 2 ), 91.4 (C(=)C), 61.0 (NC(C 3 ) 2 ), 59.9 (NC(C 3 ) 2 ), 40.5 (C(C 3 ) 2 C 2 C 2 C 2 ), 40.2 (C(C 3 ) 2 C 2 C 2 C 2 ), 35.7 (CC(C 3 )C 2 ), 34.5 (NC(C 3 ) 2 ), 34.2 (NC(C 3 ) 2 ), 32.5 (C 2 CC(C 3 ) 2 ), 26.0 (CC(C 3 ) 2 ), 25.9 (C 2 ), 20.5 (C(C 3 ) 2 ), 20.5 (C(C 3 ) 2 ), 17.7 (C(C 3 ) 2 ), 17.4 (C(C 3 ) 2 C 2 C 2 C 2 ), 15.5 (C(C 3 )C 2 ); RMS (ESI-TF) calculated for C N [M+] + 26 m/z , found [α] D = (c = 0.92, CCl 3 ) Minor: See (S)-Citronllal entry above for data. [α] D = (c = 0.34, CCl 3 ) 4. The diastereomeric ratio (15:1) was determined from the crude 1 NMR aldehyde peaks. TMP 1. BnN 2 Ac, NEt 3 DCE 2. NaB(Ac) 3 BnN TMP (S)-N-benzyl-3-phenyl-2-(2,2,6,6,-tetramethylpiperidin-1-yloxy)propan-1-amine. To a dried vial were added (S)-3-phenyl-2-(2,2,6,6-tetramethylpiperidin1-yloxy)propanal (200 mg, 0.67 mmol, 1.0 equiv.), prepared from the procedure described above, triethylamine (125 µl, 0.91 mmol, 1.4 equiv.), benzylamine acetic acid (146 mg, 0.87 mmol, 1.3 equiv.) and DCE (9.6 ml). The mixture was stirred vigorously for 15 minutes at room temperature before sodium triacetoxyborohydride (355 mg, 1.7 mmol, 2.5 equiv.) was added and stirred vigorously for an additional 3 h until starting material was consumed by TLC. The reaction was quenched with sat. aq. NaC 3 (5.0 ml) and water (3.0 ml). The aqueous layer was extracted with C 2 Cl 2 (2 x 8.0 ml) and EtAc (2 x 8.0 ml), and the combined organic layers were dried over Na 2 S 4, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography with a 50%

19 S19 EtAc in hexanes eluent to provide the desired product (256.5 mg, 99% yield) as a colorless liquid. IR (thin film) , , , , , , , , , , , 745.9, cm -1 ; 1 NMR (500 Mz, CD 3 D) δ: (m, 10, Ar), (m, 1, CTMP), (m, 2, NC 2 Ar), 3.19 (dd, 1, J = 5.5, 13.0 z, NC 2 C), 2.86 (dd, 1, J = 7.5, 12.0 z, C 2 Ar), (m, 2, C 2 Ar/NC 2 C), (m, 18, TMP); 13 C NMR (125 Mz, CD 3 D) δ: (Ar), (Ar), (Ar), (Ar), (Ar), (Ar), (Ar), (Ar), 82.9 (NC 2 C), 61.3 (NC(C 3 ) 2 ), 61.2 (NC(C 3 ) 2 ), 54.5 (NC 2 Ar), 53.6 (NC 2 C), 41.5 (bs, C(C 3 ) 2 C 2 C 2 C 2 ), 39.9 (C 2 Ar), 35.0 (NC(C 3 ) 2 ), 34.6 (NC(C 3 ) 2 ), 21.2 (NC(C 3 ) 2 ), 20.9 (NC(C 3 ) 2 ), 18.3 (C(C 3 ) 2 C 2 C 2 C 2 ); RMS (ESI-TF) calculated for C N [M+] + m/z , found [α] 23 D = (c = 0.98, CCl 3 ). The enantiomeric excess was determined from the corresponding m-nitrobenzoyl ester, which was prepared by treating the product (1.0 equiv.) with triethylamine (2.0 equiv.) and m-nitrobenzoyl chloride (1.2 equiv.) in C 2 Cl 2 (0.5 M) at room temperature for 1 h. Upon complete consumption of starting material, the reaction mixture was diluted with C 2 Cl 2 and quenched with water. The organic layer was dried over Na 2 S 4 and concentrated under vacuum. The crude mixture was purified by preparative TLC. PLC analysis of the ester (AD, 6% IPA/hexanes, 1.0 ml/min, 254 nm) indicated 93% ee: t R (major) = 16.7 minutes, t R (minor) = 20.5 minutes. TMP NaB 4, 0 o C rt TMP (S)-3-phenyl-2-(2,2,6,6,-tetramethylpiperidin-1-yloxy)propan-1-ol. To a dried vial were added (S)-3-phenyl-2-(2,2,6,6-tetramethylpiperidin1-yloxy)propanal (150 mg, 0.52 mmol, 1.0 equiv.), prepared from the procedure described above, and (1.0 ml) and cooled to 0 o C, after which NaB 4 (39.2 mg, 1.0 mmol, 2.0 equiv.) was added. The reaction was slowly warmed to room temperature over 1 h before being quenched with sat. aq. N 4 Cl (1.0 ml) and water (1.0 ml). The aqueous layer was extracted with C 2 Cl 2 (3 x 2.0 ml), and the combined organic layers were dried over Na 2 S 4, filtered, and concentrated under vacuum. The crude product was purified by flash

20 S20 chromatography with a 10% EtAc in hexanes eluent to provide the desired product (298.6 mg, 99% yield) as a colorless liquid. IR (thin film) , , , , , , , , , , , , , , 975.5, 790.1, cm -1 ; 1 NMR (500 Mz, CDCl 3 ) δ: (m, 3, Ar), (m, 2, Ar), 5.65 (bs, 1, ), (m, 1, CTMP), 3.90 (dd, 1, J = 9.5, 12.0 z, C 2 ), 3.58 (dd, 1, J = 2.0, 12.0 z, C 2 ), 2.65 (dd, 1, J = 9.5, 13.5 z, C 2 Ar), 2.52 (dd, 1, J = 5.5, 14.0 z, C 2 Ar), (m, 9, C 2 C 2 C 2 /NC(C 3 ) 2 ), 1.14 (s, 3, NC(C 3 ) 2 ), 1.04 (s, 3, NC(C 3 ) 2 ), 0.90 (s, 3, NC(C 3 ) 2 ); 13 C NMR (125 Mz, CDCl 3 ) δ: (Ar), (Ar), (Ar), (Ar), 81.1 (C(=)C), 67.9 (C 2 ), 61.5 (NC(C 3 ) 2 ), 60.0 (NC(C 3 ) 2 ), 40.3 (C(C 3 ) 2 C 2 C 2 C 2 ), 39.9 (C(C 3 ) 2 C 2 C 2 C 2 ), 37.7 (C 2 Ph), 34.6 (NC(C 3 ) 2 ), 32.4 (NC(C 3 ) 2 ), 20.6 (NC(C 3 ) 2 ), 20.2 (NC(C 3 ) 2 ), 17.2 (C(C 3 ) 2 C 2 C 2 C 2 ); RMS (ESI-TF) calculated for C N [M+] + m/z , found [α] D = (c = 1.30, CCl 3 ). PLC analysis as above indicated 93% ee. Br - + Ph 3 P 1. n-buli, TF, -78 o C 2. TF, -78 o C TMP TMP (S, Z)-2,2,6,6,-tetramethyl-1-(1-phenylpent-3-en-2-yloxy)piperidine. To a dried vial were added (ethyl)triphenylphosphonium bromide (540 mg, 0.36 mmol, 2.1 equiv.) and TF (2.8 ml). The mixture was cooled to -78 o C, and n-buli (2.5M in TF, 0.55 ml, 0.35 mmol, 2.0 equiv.) was added dropwise. The mixture was warmed to 0 o C and stirred for 1 h, after which it was cooled to -78 o C, and the aldehyde (200 mg, 0.17 mmol, 1.0 equiv.) in TF (1.2 ml) was added dropwise. The mixture was stirred for 15 minutes then slowly warmed to 0 o C and stirred for an additional 40 minutes, after which it was warmed to room temperature, and stirred for an additional 30 minutes until starting material was consumed by TLC. The reaction was cooled to -78 o C and quenched with sat. aq. N 4 Cl (1.0 ml) and water (1.0 ml). The aqueous layer was extracted with C 2 Cl 2 (3 x 2.0 ml), and the combined organic layers were dried over Na 2 S 4, filtered,

21 S21 and concentrated under vacuum. The crude product was purified by flash chromatography with hexanes to provide the desired product (47 mg, 91% yield, 10:1 Z : E) as an inseparable mixture of olefin isomers as a colorless liquid. IR (thin film) , , , , , , , , , , , , 973.9, 956.4, 925.9, 724.2, cm -1 ; 1 NMR (500 Mz, C 6 D 6 ) δ: (m, 5, Ar), (m, 1, CCC 3 ), (m, 1, CCC 3 ), (m, 1, CTMP), 3.37 (dd, 1, J = 4.5, 12.5 z, C 2 Ar), 2.78 (dd, 1, J = 8.5, 13.0 z, C 2 Ar), (m, 3, C 3 ), (m, 18, TMP); 13 C NMR (125 Mz, C 6 D 6 ) δ: (Ar), (CCC 3 ), (Ar), (Ar), (Ar), (CCC 3 ), 80.8 (CTMP), 60.3 (NC(C 3 ) 2 ), 59.5 (NC(C 3 ) 2 ), 42.0 (C 2 Ar), 42.0 (C(C 3 ) 2 C 2 C 2 C 2 ), 40.7 (C(C 3 ) 2 C 2 C 2 C 2 ), 35.4 (NC(C 3 ) 2 ), 34.5 (NC(C 3 ) 2 ), 20.8 (NC(C 3 ) 2 ), 20.5 (NC(C 3 ) 2 ), 17.7 (C(C 3 ) 2 C 2 C 2 C 2 ) 13.3 (C 3 ); RMS (ESI-TF) calculated for C N [M+] + m/z , found The diastereomeric ratio was determined by the ratio of crude 1 NMR peaks at 3.37 ppm and 3.24 ppm. The enantiomeric excess was determined from the corresponding diol, which was prepared by treating the product (1.0 equiv.) with Zn (10.0 equiv.) in a 1:1 mixture of Ac : 2 (0.5 M) at 50 o C. Upon complete consumption of starting material, the reaction mixture was cooled to room temperature and extracted with C 2 Cl 2 (x 3). The combined organic layers were washed with sat. aq. NaC 3, and the aqueous layer was extracted with C 2 Cl 2 (x 3). The combined organic layers were dried over Na 2 S 4 and concentrated under vacuum. The crude mixture was purified by preparative TLC. PLC analysis of the major diol diastereomer (J, 3% IPA/hexanes, 1.0 ml/min, 220 nm) indicated 93% ee: t R (major) = 46.7 minutes, t R (minor) = 50.4 minutes. TMP MgCl, TF -78 o C TMP (2S, 3S)-4-phenyl-2-(2,2,6,6,-tetramethylpiperidin-1-yloxy)butan-2-ol. To a dried vial were added (S)-3-phenyl-2-(2,2,6,6-tetramethylpiperidin1-yloxy)propanal (200.0 mg, 0.69 mmol, 1.0 equiv.), prepared from the procedure described above, and TF (3.5 ml). The solution was cooled to -78 o C, and MgCl (3M in TF, 0.46 ml, 1.4 mmol, 2.0

22 S22 equiv.) was added dropwise. The reaction mixture was stirred at -78 o C for 1.75 h then warmed to 0 o C and stirred for an additional 15 minutes until starting material was consumed by TLC. The reaction was cooled to -78 o C and quenched with sat. aq. N 4 Cl (1.0 ml) and water (1.0 ml). The aqueous layer was extracted with C 2 Cl 2 (3 x 2.0 ml), and the combined organic layers were dried over Na 2 S 4, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography with a 20% EtAc in hexanes eluent to provide the desired product (200.1 mg, 92% yield, 5:1 dr) as an inseparable mixture of diastereomers as a white solid. IR (thin film) , , , , , , , , , , , , , , 973.1, 910.5, 745.4, cm -1 ; Major: 1 NMR (500 Mz, CDCl 3 ) δ: (m, 5, Ar), (m, 1, CTMP), 3.89 (ap bs, 1, C), 3.43 (dd, 1, J = 4.0, 13.0 z, C 2 Ar), (m, 1, C 2 Ar), 2.14 (s, 1, ), (m, 21, TMP/C 3 ); 13 C NMR (125 Mz, CDCl 3 ) δ: (Ar), (Ar), (Ar), (Ar), 86.0 (CTMP), 68.2 (C), 60.7 (NC(C 3 ) 2 ), 59.9 (NC(C 3 ) 2 ), 40.7 (C(C 3 ) 2 C 2 C 2 C 2 ), 40.5 (C(C 3 ) 2 C 2 C 2 C 2 ), 35.8 (C 2 Ar), 34.6 (NC(C 3 ) 2 ), 34.1 (NC(C 3 ) 2 ), 20.8 (NC(C 3 ) 2 ), 20.5 (NC(C 3 ) 2 ), 17.4 (C 3 ), 17.2 (C(C 3 ) 2 C 2 C 2 C 2 ); Minor: 1 NMR (500 Mz, CDCl 3 ) Peaks corresponding to major diastereomer in crude 1 NMR overlapped except for δ: (m, 2, C/CTMP), (m, 1, C 2 Ar), (m, 1, C 2 Ar). 13 C NMR (125 Mz, CDCl 3 ) δ: (Ar), (Ar), (Ar), (Ar), 85.5 (CTMP), 71.5 (C), 60.7 (NC(C 3 ) 2 ), 59.9 (NC(C 3 ) 2 ), 40.3 (C(C 3 ) 2 C 2 C 2 C 2 ), 39.9 (C(C 3 ) 2 C 2 C 2 C 2 ), 37.8 (C 2 Ar), 34.2 (NC(C 3 ) 2 ), 32.0 (NC(C 3 ) 2 ), 20.5 (NC(C 3 ) 2 ), 20.3 (NC(C 3 ) 2 ), 17.4 (C 3 ), 17.2 (C(C 3 ) 2 C 2 C 2 C 2 ). The diastereomeric ratio was determined by the ratio of crude 1 NMR peaks at 3.43 ppm and 3.51 ppm. RMS (ESI-TF) calculated for C N [M+] + m/z , found The enantiomeric excess was determined from the corresponding diol, which was prepared by treating the product (1.0 equiv.) with Zn (10.0 equiv.) in a 1:1 mixture of Ac: 2 (0.5 M) at 50 o C. Upon complete consumption of starting material, the reaction mixture was cooled to room temperature and extracted with C 2 Cl 2 (x 3). The combined organic layers were washed with sat. aq. NaC 3, and the aqueous layer was extracted with C 2 Cl 2 (x 3). The combined organic layers were dried over Na 2 S 4 and

23 S23 concentrated under vacuum. The crude mixture was purified by preparative TLC. PLC analysis of the diol major diastereomer (J, 3% IPA/hexanes, 1.0 ml/min, 220 nm) indicated 93% ee: t R (major) = 46.7 minutes, t R (minor) = 50.4 minutes. 1. LDA, TF, -78 o C 2. TF, -78 o C TMP TMP (3R, 4S)-3-hydroxy-1,5-diphenyl-4-(2,2,6,6,-tetramethylpiperidin-1-yloxy)pentan-1- one. To a dried vial were added diisopropylamine (65 µl, 0.46 mmol, 1.0 equiv.) and TF (1.60 ml) and cooled to -78 o C, after which n-buli (2.5M in hexanes, 184 µl, 0.46 mmol, 1.0 equiv.) was added dropwise. After 30 minutes, acetophenone (54 µl, 0.46 mmol, 1.0 equiv.) was added dropwise, and the resulting solution was stirred at -78 o C for an additional 30 minutes. To the vial was added (S)-3-phenyl-2-(2,2,6,6- tetramethylpiperidin1-yloxy)propanal (200 mg, 0.69 mmol, 1.5 equiv.), prepared from the procedure described above, in TF (0.4 ml) dropwise, and the reaction mixture was stirred at -78 o C until starting material was consumed by TLC (1.3 h). The reaction was quenched with sat. aq. N 4 Cl (1.0 ml) and slowly warmed to room temperature, followed by the addition of water (1.0 ml) and ether (1.0 ml). The aqueous layer was extracted with ether (3 x 2.0 ml), and the combined organic layers were dried over Na 2 S 4, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography with a 25% EtAc in hexanes eluent to provide the desired product (164.0 mg, 87% yield, 13:1 dr) as an inseparable mixture of diastereomers as a white solid. IR (thin film) , , , , , , , , , , , , , 988.7, 973.0, 788.4, cm -1 ; 1 NMR (500 Mz, C 6 D 6 ) δ: 7.90 (d, 2, J = 5.0 z, Ar), (m, 2, Ar), (m, 6, Ar), (m, 1, C), (m, 1, CTMP), 3.63 (dd, J = 6.0 z, J = 14.0 z, C 2 Ar), 3.16 (dd, 1, J = 10.0 z, J = 18 z, C(=)C 2 ), (m, 1, C(=)C 2 ), (m, 2, C 2 Ar/), (m, 18, TMP); 13 C NMR (125 Mz, C 6 D 6 ) δ: (C(=)), (Ar), (Ar), (Ar), 130.0